丹参酮ⅡA抑制肾性高血压大鼠氧化应激和心肌肥厚

Tanshinone Ⅱ A Attenuated Oxidative Stress and Left Ventricular Hypertrophy Induced by Renovascular Hypertension

背景血管还原型烟酰胺腺嘌呤二核苷酸(磷酸)[NAD(P)H]氧化酶激活产生的活性氧增多所产生的氧化损伤在左心室肥厚的发生发展中起重要作用,丹参酮ⅡA被证实能通过抗氧化作用阻滞粥样硬化斑块的发展,但它对左心室肥厚的发生发展有无影响尚未见实验证实。目的观察丹参酮ⅡA(TanⅡA)对两肾两夹手术造成的肾性高血压大鼠左心室肥厚的作用,并与缬沙坦的作用相比较,探讨TanⅡA防治心室肥厚的作用机制。方法实验分5组:对照组、模型组、缬沙坦组[30 mg/(kg.d)]、TanⅡA高剂量组[TanH,70 mg/(kg.d)]和TanⅡA低剂量组[TanL,35 mg/(kg.d)]。术后4周开始药物处理,连续给药6周,测定血压和左室质量指数,行超声心动图检查,采用共聚焦显微镜检测左心室和主动脉中O2.-的产生情况,用化学发光仪测定NAD(P)H氧化酶的活性。结果两肾两夹大鼠手术后4周血压升至180 mm Hg左右,显著高于对照组(P<0.05),模型组大鼠术后10周,左心室肥厚较对照组明显(P<0.05),心肌和主动脉壁中O2.-的产生明显增多(P<0.01),NAD(P)H氧化酶活性明显升高(P<0.05);TanⅡA治疗高血压大鼠6周后显著抑制左心室肥厚的发展(P<0.05),明显减少心肌和主动脉中的O2.-产生(P<0.05),降低NAD(P)H氧化酶活性(P<0.05),高剂量作用显著,但未见明显降低血压作用;缬沙坦不但能减轻氧化应激和心室肥厚发展,还能明显降低血压(均P<0.05)。结论丹参酮ⅡA抑制心肌肥厚的作用可能与降低NAD(P)H氧化酶活性从而减少O2.-的产生有关。

Background There is increasing evidence that oxidative stress,overproduction of reactive oxygen species（ROS） originating from nicotinamide adenine dinucleotide phosphate [NAD（P）H] oxidase,plays a critical role in the development and progression of cardiac remodeling associated with heart failure.Many experimental and clinical studies have reported that tanshinone ⅡA（TanⅡA） is an anti-oxidant effective for inibition of atherosclerosis.However,no studies have addressed the effect of TanⅡA on cardiac hypertrophy.Objective To study the effects of TanⅡA on left ventricular hypertrophy induced by renovascular hypertension after two-kidney two-clip（2K2C） operation,and the impossible underlying mechanism.Methods There were 5 groups in the experiment： control： rats received sham operation and given 0.5% carboxymethylcellulose sodium;2K2C： rats received 2K2C operation and given 0.5% carboxymethylcellulose sodium;valsartan： 2K2C rats given valsartan [30 mg/（kg·d）];TanH： 2K2C rats given TanⅡA [70 mg/（kg·d）] and TanL： 2K2C rats given TanⅡA [35 mg/（kg·d）].At the endpoint of the experiment,echocardiography was performed.Then the rats were sacrificed,body mass（BM） and left ventricule mass（LVM） were determined,and the LVMI was calculated.The oxidative fluorescence dye dihydroethidium detected by laser confocal fluorescent microscopy was used to evaluate in situ O2.-generation in the LV and aorta.The NAD（P）H oxidase activity in LV and aorta was estimated with lucigenin-enhanced chemiluminescence.Results Compared with the control rats,BP of 2K2C rats was elevated to about 180 mm Hg at week 4 after operation（P0.05）.Ten weeks after operation,2K2C rats developed obvious LV hypertrophy,with enhanced O2.-generation and NAD（P）H oxidase activity in LV and aorta（P0.05）.Tan ⅡA,more significantly in high dose,attenuated LVH（P0.05） and reversed the over oxidative stress by inhibiting generation of O2.-（P0.01）and the activation of NAD（P）H oxidase（P0.05） in LV and aorta after treatment for 6 weeks though BP wasnot decreased significantly,while valsartan,not only attenuated LVH and oxidative stress,but also decreased BP markedly.Conclusion Tan ⅡA significantly reverse the LV hypertrophy in 2K2C rats,that might be associated with attenuation of NAD（P）H oxidase-derived reactive oxygen species production.